Cognitive functioning in children prenatally exposed to alcohol and psychotropic drugs.

Cognitive functioning was compared in 29 children diagnosed with fetal alcohol syndrome (FAS), 35 children with fetal alcohol effects (FAE), and 66 psychotropic drugs-exposed (PDE) children using Wechsler tests and the neuropsychological test battery NEPSY. In the FAS group, verbal IQ (VIQ=78), performance IQ (PIQ=77), and full scale IQ (FSIQ=75) were significantly lower as compared to the FAE and PDE groups. In the PDE group VIQ and FSIQ were significantly higher than in the FAE group. In the FAS group, processing speed (PS) was significantly lower than the other three factors. In the FAE group, perceptual organization (PO) was significantly higher, whereas PS was significantly lower than the other factors. In the PDE group, verbal comprehension (VC) was significantly higher than the other factors. Attention subscales on the NEPSY were significantly lower in all the three groups. Prenatal alcohol exposure affects IQ levels more than exposure to psychotropic drugs. Attentional problems were found in all children when tested with the NEPSY in all groups.

Intelligence in children with hydrocephalus, aged 4-15 years: a population-based, controlled study.

The aim of this population-based study is to investigate IQ and IQ-related factors in children with hydrocephalus (HC). Psychometric intelligence was assessed in subjects below the age of 7.3 years (N=52, F=18, M=34) with the Wechsler Preschool and Primary Scale of Intelligence - Revised (WPPSI-R) and for children above the age of 7.3 years (N=29, F=6, M=23) with the Wechsler Intelligence Scale for Children - Revised (WISC-R). The controls were matched according to age, gender, and geographic variables. All children were living in western Norway. 57 children had infantile HC (IH) and 24 had childhood HC (CH). Children with myelomeningocele (MMC), traumatic brain injury (TBI), or intracranial tumours were excluded. IQ levels were found to be significantly higher in the control group than in the HC groups. The Kaufman factors showed a similar pattern, with lowest values in IH, and CH intermediate between IH and NC. The results demonstrate that HC affects IQ. More specific cognitive profiles, such as non-verbal learning disabilities, are not detectable when using the Wechsler tests. For this purpose, other tests and models for analyses may be recommended.

Complexity of foetal alcohol or drug neuroimpairments.

AIMS: To describe children exposed to street drug during pregnancy (SDE) and compare these with children suffering from Foetal Alcohol Syndrome (FAS) and Foetal Alcohol Spectrum Disorders (FASD) regarding growth, somatic health and neuroimpairments. METHODS: In the region, Hordaland county an information program was carried out to educate health-care and social workers on symptoms and signs of SDE and FAS/FASD and referral was encouraged for suspected cases. Referred children received a neuropaediatric evaluation, and were categorized as FAS/FASD and SDE children. RESULTS: Among the referred children 50 were diagnosed with SDE and 47 children were diagnosed with FAS/FASD. SDE children had increased risk of neonatal abstinence symptoms but were somatic healthy and had no growth restriction and were performing well academically. Almost all children in both groups met the criteria of Attention Deficit Hyperactivity Disorder (ADHD). CONCLUSION: Children exposed to drugs are somatic healthy but have increased risk of neuroimpairments such as ADHD.

Lack of recognition and complexity of foetal alcohol neuroimpairments.

AIMS: To obtain the recorded prevalence of foetal alcohol syndrome (FAS) and foetal alcohol spectrum disorders (FASD) in Norway, and evaluate the effect of a general information program to increase the recognition of FAS/FASD for health care and social workers. METHODS: A questionnaire regarding prevalence of FAS/FASD was sent to all Norwegian paediatric and child psychiatry departments. In the region Hordaland county, an information program was carried out to educate health-care and social workers on symptoms and signs of FAS/FASD, and referral was encouraged for suspected cases. Referred children received a neuropaediatric evaluation, and the effect of the information program on recorded FAS/FASD was recorded. RESULTS: Based on the national survey, a prevalence of 0.3 per 1000 was calculated. After the information program, the estimated prevalence in Hordaland County increased to 1.5 per 1000. In 5 years, 25 children were diagnosed with FAS and 22 with FASD. One-third of all children were mentally retarded. Microcephaly and neuroimpairments were more common among FAS children. Almost all children met the criteria of ADHD. CONCLUSION: The rate of FAS/FASD may be greatly underestimated because of lack of knowledge. An information program aimed at health-care and social workers is effective.

Non-verbal learning disabilities in children with infantile hydrocephalus, aged 4-7 years: a population-based, controlled study.

The aim of this population-based, controlled study was to investigate non-verbal learning disabilities (NLD) in children with infantile hydrocephalus (IH). For this purpose, the results from subtests measuring either assets or deficits within Rourke's model of NLD were analyzed. Children with myelomeningocele (MMC), intracranial tumors, or IQ < 70 were excluded. Of the 52 IH children included in the study, 46 were shunt-treated, whereas 6 were not shunted. The 44 controls were matched according to age, gender, and geographic variables. The Neuropsychological Assessment of Children (NEPSY) was administered to 52 children (age 4-7) with IH; (F = 17, M = 35), and to 44 controls (F = 17, M = 27). The tests used were classified along each of the dimensions "assets" or "deficits", according to Rourke's model of the elements and the dynamics of the NLD syndrome. Differences between sum scores for the subtests classified as "assets", versus "deficits" were significantly higher in the IH group as compared with the controls (p < 0.005). These findings are compatible with a higher frequency of NLD in the IH group, in which neurological confounding factors have been excluded. In addition, the model of the elements and the dynamics of the NLD syndrome may be useful when analyzing neuropsychological test results obtained with traditional and comprehensive test batteries.

Does a sedative dose of chloral hydrate modify the EEG of children with epilepsy?

Chloral hydrate (CH) is used to sedate children unable to cooperate during investigations such as EEG requiring the patient to be still. It is not known if CH or its metabolites modify the EEG and our aim was to answer this question. Recordings of the EEG before, during and after rectal administration of CH (50-77 mg/kg) in 13 children aged 1.5-13.5 years with severe epilepsy and additional neurological impairments were made. All children had frequent spike-wave activity before CH. In 9 children CH had no effect on the EEG. In 3 children there was a significant reduction in epileptic activity after 20-50 min and in one a significant increase. Cardiovascular parameters were stable throughout. At sedative doses, CH can generally be used before an EEG recording without loss of information but in 4 out of 13 children there were changes which could alter interpretation.

Growth hormone status in six children with fetal alcohol syndrome.

OBJECTIVE: Prenatal alcohol exposure may cause fetal alcohol syndrome (FAS), which is associated with pre- and postnatal retardation. MATERIALS AND METHODS: Spontaneous 24-h growth hormone (GH) secretion was measured in six prepubertal short children with FAS (two boys and four girls) aged 4-14 years. The response to a GH stimulation test, and levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) were also measured. Comparisons were made between the children with FAS and healthy children of both normal and short stature, as well as children born small for gestational age (SGA). RESULTS: There were no differences in the mean area under the curve above the baseline or the maximum level of GH during a 24-h period (GHmax) between the children with FAS and the reference groups. However, the estimated rate of spontaneous 24-h GH secretion in children with FAS was similar to that of children born SGA, but lower than in children of normal stature (p = 0.02). The plasma concentrations of IGF-I and IGFBP-3 were in the lower parts of the normal range. CONCLUSION: We conclude that GH secretion in short children with FAS is similar to that in short children born SGA; that is, in the lower range of normal children.

Benzodiazepine amplification of valproate teratogenic effects in children of mothers with absence epilepsy.

Valproate (VPA) is one of the most frequently used antiepileptic drugs (AEDs). Concern has recently been raised regarding VPA medication during pregnancy and teratogenic effects in the offspring. Both neural tube defects (5, 18, 34) and a constellation of signs termed the fetal valproate syndrome (1, 12) have been reported. Benzodiazepines (BZDs) are also widely used and sometimes as effective adjunctives in AED therapy. Both VPA and BZD have close connections to GABA transmission. Recently, clinical and epidemiological human studies (26, 27, 37, 39), supported by animal studies (17, 24, 40), have indicated that BZDs may act as human teratogens. We report on 7 children with congenital malformations, dysmorphism and abnormal neurological signs from birth. The mothers had well controlled primary generalized absence epilepsy without major seizures during pregnancy. Five children had been exposed to VPA monotherapy and two children to VPA and BZD combined during the first trimester. Those two infants had myelomeningoceles and the most pronounced dysmorphism in the group. We propose that these observations indicate a possible amplifying action of BZDs on VPA teratogenicity. Unrecognized BZD use during pregnancies exposed to VPA may be of importance when estimating the teratogenic risks of VPA therapy.

Mental development in late infancy after prenatal exposure to benzodiazepines--a prospective study.

Seventeen infants born to mothers who used benzodiazepines (BZD) throughout pregnancy were followed prospectively and compared with 29 infants born to mothers who had not used psychoactive substances. On the Griffiths' Developmental Scale, the BZD-exposed infants demonstrated consistently lower mean GQs and DQs for all subscales at 5, 10 and 18 months of age. The differences in GQ reached statistical significance at 10 and 18 months. The DQs differed significantly for all subscales at 10 months and for the personal-social behaviour and hearing and speech subscales at 18 months of age. We suggest that prenatal exposure to BZD may cause a general delay in mental development up to 18 months of age.

Psychotropic drug use in pregnancy and perinatal death.

The psychotropic drug use in mothers to all 73 perinatally dead infants in the city of Gothenburg, Sweden, in 1985-86, was compared to a control group of mothers to 73 surviving infants. Information regarding medication in pregnancy and pre- and perinatal data was collected retrospectively. In addition, serum samples obtained in early pregnancy were screened for benzodiazepines. Eighteen case-mothers used psychotropic drugs during pregnancy compared with 7 control-mothers. The association between psychotropic drug use and perinatal death was significant (p = 0.01). Psychotropic drug use and maternal disorder were closely correlated, but within the case group there were no significant differences between mothers using or not using psychotropic drugs in terms of age, parity or smoking habits. Although the etiology of death could be discussed in the individual infant, we find it noteworthy that the use of psychotropic drugs was so frequent in the mothers of perinatally dead infants.

Neurodevelopment in late infancy after prenatal exposure to benzodiazepines--a prospective study.

Growth and neurodevelopment at 6, 10 and 18 months of age have been studied prospectively and longitudinally in a series of 17 children born to mothers who used benzodiazepines (BZD) in therapeutic doses as their only psychotropic drug throughout pregnancy. The results were compared with a group of 29 children born to mothers without any known use of psychotropic drugs. The BZD-exposed children caught up their low mean birth-weight, at an early stage, whereas the slightly decreased head circumference at birth remained at the same low level. In five infants, a pattern of craniofacial anomalies was found. Deviating neurodevelopmental and clinical symptoms and signs were common. The gross motor development was retarded at 6 and 10 months, but was nearly normal at 18 months. Impaired fine motor functions were found on all follow-up occasions. At 18 months, the most prominent finding was a delayed development of pincer grasp. The BZD-exposed children showed deviations in muscle tone and pattern of movements more frequently than children in the reference group. The study suggests that the use of BZD in therapeutic doses throughout pregnancy can have negative effects on the development of children up to 18 months of age. The long-term hazards cannot be evaluated from these results. A further follow-up at early school age is needed and is in progress.

The effect of benzodiazepines on the fetus and the newborn.

The effect of the maternal use of benzodiazepines (BZD) on the fetus and the newborn infant has been studied in a representative series of 17 newborn infants (BZD group). The pregnancy and the perinatal period were characterized by 20 items. On the 2nd day of life, a neurologic investigation was performed and comprised a total of 38 items, subgrouped into items of reflexes/reactions, tonus, and other symptoms and signs. An optimum finding for each item was selected. The results were compared with a group of 21 newborns fetally exposed to psychotropic drugs other than BZD (drug group) and a reference group of 29 newborns with no known fetal exposure to drugs. Infants in the BZD group had a lower birth weight for birth length, as compared to both the drug group and the reference group. Significant differences in frequency of pre- and perinatal complications and in neuro-behavior between the BZD group and the reference group were found in all groups of items. We conclude that the use of BZD during pregnancy is associated with impaired intrauterine growth and an increased frequency of pre- and perinatal events. It affects the newborn infant neurologically mainly in the form of intoxication and withdrawal symptoms.

Congenital malformations and maternal consumption of benzodiazepines: a case-control study.

This study assessed potential teratogenic properties of benzodiazepine (BZD) intake during early pregnancy. Four neonatal diagnoses of congenital malformations (embryopathy and fetopathy, unspecified; unspecified congenital malformations of the nervous system; cleft palate and cleft lip; congenital malformations of the urinary tract) were selected. The authors' previous clinical experience had shown these diagnoses to be characteristic of infants born to mothers with excessive intake of BZD in early pregnancy. The selected diagnoses were present in 25 of 10,646 liveborn infants (2.3 per 1000) delivered by mothers living in the city of Gothenburg in 1985 and 1986. In 18 of these cases, it was possible to analyse maternal plasma, and eight samples (44 per cent) were found to be BZD-positive. Of 60 controls, two maternal blood samples (3 per cent) were positive for BZD. The difference is highly significant and suggests an association between these congenital malformations and BZD consumed during early gestation.

Clinical observations in children after prenatal benzodiazepine exposure.

Eight children excessively exposed to benzodiazepines (BZD) in utero are described. Five of the 8 mothers admitted regular use of BZD and in 3 mothers, stored serum from early pregnancy could be analysed and found positive for BZD and its metabolite. All the children had similar dysmorphic features, in addition, 1 child had aplasia of one kidney and 2 had cleft palate. At follow-up 2 children had become microcephalic. 2 were severely mentally retarded, 5 had a mild mental retardation and only 1 was of normal intelligence. In a case-control study, 4 neonatal diagnoses of congenital malformations, in our experience characteristic of fetal BZD exposure, were chosen as inclusion criteria. In 8 of 18 cases, blood samples from early pregnancy were positive for BZD as compared to 2 of 60 control samples. An association between BZD-positive serum tests and the particular diagnoses could be demonstrated (p = 0.00006).

Teratogenic effects of benzodiazepine use during pregnancy.

Eight children exposed in utero to benzodiazepines had characteristic dysmorphic features, growth aberrations, and central nervous system abnormalities from birth. Their dysmorphic characteristics resembled those of the fetal alcohol syndrome, although they had greater focal involvement of cranial nerves, with a sullen and expressionless face, and they more often had impairment of vitality at birth. One infant died and at autopsy had varying degrees of distortion of neuronal migration, with concomitant heterotopias. Five of the eight mothers had regularly consumed benzodiazepines, and the three remaining mothers had blood samples during pregnancy revealing benzodiazepine concentrations indicative of regular use. Our findings indicate that maternal consumption of benzodiazepines may be teratogenic in humans.

Prenatal factors including fetal alcohol syndrome.

The first discovered exogenous teratogen causing mental retardation was rubella embryopathy described in 1940. Later, cytomegalic virus infection and toxoplasmosis during pregnancy and ionogenic radiation has been shown to cause embryofetopathies with concomitant mental retardation. Methyl mercury in high doses cause severe central nervous system pathology in both mothers and their fetuses. The fetal alcohol syndrome is now generally accepted as causing mostly mild mental retardation. Of therapeutic drugs, antiepileptics have been shown to carry a risk for the fetal antiepileptic syndrome complex. We have recently been able to describe fetal pathology following high intake of benzodiazepines during pregnancy.